Neurons located in the wall of the bowel project out of the gut to innervate targets in the pancreas. The majority of these enteropancreatic fibers terminate on intrapancreatic ganglia. When enteric neurons are stimulated, neurons in pancreatic ganglia, as well as the islet and acinar cells they innervate, are activated. Retrograde tracing studies, involving the injection of Fluoro-Gold (FG) into the pancreatic parenchyma, have established that the enteric neurons that project to the pancreas are located in the myenteric plexus of the duodenum and stomach. A subset of these enteropancreatic neurons must be cholinergic, because enteric activation of pancreatic cells can be antagonized by hexamethonium. An additional subset is serotonergic, since injections of FG into the pancreas specifically label serotonergic neurons in the myenteric plexus of the bowel. At present, the role of the enteropancreatic innervation is unknown. In order to investigate what this role may be, we will (I) ascertain the types of stimuli responsible for the physiological activation of enteropancreatic reflexes, (ii) determine the respective roles of the serotonergic and cholinergic constituents of the enteropancreatic innervation, (iii) establish the effects on pancreatic exocrine and endocrine secretion of physiological activation of enteropancreatic reflexes, and (iv) determine the role of glucoresponsive pancreatic neurons in the enteric neural regulation of insulin secretion. The effects of enteric stimulation on the activity of pancreatic neurons will be performed in vitro and will combine intracellular recording with dye filling and immunocytochemistry. These studies will establish the effects of enteric stimulation on the activity of pancreatic neurons and if pancreatic neurons that receive enteric input can be distinguished on the basis of their electrophysiological properties, neurochemistry, or targets within the pancreas. Acute pancreatitis is an often devastating medical condition. Although it is often associated with alcoholism, biliary tract disease, or Surgery, acute pancreatitis also arises idiopathically. The pathogenesis of neither the disease associated with other conditions, nor that of the idiopathic variety is known. In addition to its acute form, pancreatitis also occurs chronically and causes considerable morbidity. Treatment consists of trying to put the pancreas to rest, but other than for analgesics, no specific pharmacological means exist to treat pancreatitis. The extent to which the enteric innervation of the pancreas influences the generation or course of pancreatitis has never been investigated and thus is unknown; however, in view of the powerful action the enteropancreatic innervation exerts on exocrine pancreatic activity, it is likely that the enteropancreatic innervation is an important factor in pancreatic disease. If so, then the enteropancreatic innervation may also be a target for drugs that affect the induction or progress of pancreatitis.